A process for preparing lysergol derivatives

Description

[0001] The invention relates to a method of preparing lysergol derivatives, particularly 10a-methoxy- lumilysergol, 1-methyl-10a-methoxy-lumilysergol and esters thereof having the formula (I)

where R¹ denotes hydrogen or methyl and -OR² represents a free or esterified hydroxyl group. For example, the moiety R² can denote hydrogen, or an alkane or arene-sulphonyl or an R-CO radical where R stands for alkyl, aryl or alkaryl, which may be unsubstituted or substituted by halogen if required.

[0002] Compounds of formula (I) in which R¹ and R² are hydrogen or R¹ is methyl and R² is hydrogen, are known and their preparation is described in the literature, e.g. in Italian patent application No. 22011 A/78 (European patent application No. 79101015.0, published as EP 0004664). However the various methods previously proposed are unsatisfactory either with regard to the total reaction yield or the purity of the products or for both reasons.

[0003] For example, a description has been given of the photo-chemical reaction of lysergol in methanol/sulphuric acid and subsequent methylation of the indolic nitrogen of the thus-obtained 10a-methoxy- lumilysergol, with methyl iodide in the presence of KOH and in dimethyl sulphoxide in accordance with Reaction Scheme A

[0004] The yield from the first step is 80% whereas the transition from (III) to (IV) occurs with a 70% yield, so that the total yield of 1-methyl-10a-methoxy-lumilysergol is only 56%.

[0005] According to another method described and claimed by the present applicants in Italian Patent Application No. 20242 A/84 (European Patent Application No. 85302101.2, published as EP 0156645), lysergol esters are alkylated on the indolic nitrogen with methyl iodide and potassium in liquid ammonia, followed by photo-chemical addition of methanol in sulphuric acid and subsequent hydrolysis of the ester group. The product, 1-methyl-10-a-methoxy lumilysergol (IV), is obtained in a greater yield than that of the first method, but a rather laborious purification is required in one or more stages of the process.

[0006] It has now been found possible to obtain 10a-methoxy-lumilysergol of high purity and in a yield equal to or greater than 94% if the photo-chemical reaction is carried out in methanol/sulphuric acid under very specific reaction conditions given hereinafter, not using lysergol as such as starting material but an ester thereof (most preferably the 8-methane sulphonyl derivative).

[0007] It has unexpectedly been found that the reaction, performed on esters which are stable under the reaction conditions, occurs in the substantial absence of by-products such as ethers, or of elimination reactions involving the alcohol group. This is achieved, according to the invention, by irradiating lysergol esters in methanol at low temperature, preferably between -10 and -30°C, under controlled acidity conditions, with UV light of wavelength from 300 to 370 nm, preferably at 330 nm. When the addition of methanol is complete, it is only necessary to bring the reaction mixture back to room temperature to deacylate the ester group and obtain a substantially quantitative yield of 10a-methoxy-lumilysergol (III).

[0008] The process according to the invention can also be used to isolate the 10α-methoxy esters obtained by the procedure described (preferably the methane sulphonic ester) and subject them to N-alkylation in liquid ammonia, obtaining the corresponding esters of 1-methyl-10a-methoxy-lumilysergol (la). These esters, finally, can be transesterified to esters (lb) of 1-methyl-10a-lumilysergol having special therapeutic importance.

[0009] Thus according to the present invention there is provided a method of preparing a lysergol derivative of formula (I)

in which R¹ represents hydrogen or methyl, and -OR² represents a free or esterified hydroxyl group characterised in that a lysergol ester of formula (VII)

in which -OR³ represents an esterified hydroxyl group, is subjected to photo-chemical reaction by irradiating with UV light of wavelength from 300 to 370 nm at a temperature below 0°C in methanol containing from 2 to 10% (w/v) of H₂SO₄ to produce an ester of 10a-methoxy lumilysergol of formula (VIII)

and the resulting ester of 10α-methoxy lumilysergol of formula (VIII) is converted to a compound of formula (I) by one or more of the following optional steps carried out in any appropriate order:

(a) N-methylation;

(b) hydrolysis to form a compound in which OR² represents hydroxyl;

(c) esterification of a compound in which OR² represents hydroxyl to form a compound in which OR² represents an esterified hydroxyl group;

(d) transesterification of a compound in which OR² represents an esterified hydroxyl group.

[0010] Preferably the photochemical reaction is carried out in methanol containing 3% w/v of H₂SO₄. (The expression "x% (w/v)" means x grams/100 mls).

[0011] The reactions according to the invention in its preferred embodiments can be summarised in the following Reaction Scheme B.

[0012] In the above Reaction Scheme, R² and R³ are as defined above, but preferably R³ represents a lower alkanoyl radical, most preferably formyl, acetyl, or an alkane sulphonyl or arene sulphonyl radical such as benzene sulphonyl, p-toluene sulphonyl or preferably methane sulphonyl. R² represents an acyl radical different from R³, preferably a 5-bromopyridine-3-carbonyl radical. The preferance given to acetyl, methane sulphonyl, tosyl and similar alkane or arene sulphonyl radicals as R³ stems from the fact that these radicals are good leaving groups, more particularly with a view to transesterifying compounds (la) with suitable carboxylates to obtain esters (lb).

[0013] Alkyl and alkanoyl groups referred to herein are preferably lower alkyl and lower alkanoyl groups, by which is meant such groups containing up to 4 carbon atoms.

[0014] The initial lysergol esters of formula (VII) can be prepared by known methods, e.g. by reacting lysergol of natural'origin with carboxylic or sulphonic acid chlorides in pyridine or by other conventional reactions.

[0015] The photo-chemical reaction for converting (VII) to (VIII) is performed in methanol/sulphuric acid with a concentration of acid from 2 to 10% w/v, at temperatures below 0°C, preferably between -10°C and -30°C. The subsequent N-methylation is preferably carried out by contacting a compound of formula (VIII) with an alkyl halide, preferably an alkyl iodide such as methyl iodide in liquid ammonia in the presence of sodium or potassium amides produced in the same reaction medium.

[0016] Finally, the transesterification reactions are conveniently performed in aprotic solvents such as dimethyl formamide or dimethyl sulphoxide, with salts of the acids from which it is desired to obtain the corresponding esters.

[0017] The following examples illustrate the invention without limiting it in any way.

Example 1

10a-methoxy-lumilysergol

[0018] 10 g of lysergol 8-methane sulphonate were dissolved in 250 ml of a mixture of 3% w/v of concentrated sulphuric acid in methanol previously cooled to -30°C. The solution, kept at a temperature of -20°C and under nitrogen, was irradiated by a UV lamp emitting at 330 nm for about 2 hours. When the reaction was complete, the reaction mixture was diluted with 250 ml of water, made alkaline with NaOH to pH 8.5 and extracted with 3 x 150 ml of methylene chloride. The organic phase containing 10a-methoxylumilysergol methanesulphonate was concentrated to dryness in vacuo and the residue was taken up with 100 ml of anhydrous dimethylformamide and 5 g of potassium acetate. After keeping at 50°C for 4 hours under nitrogen, the reaction mixture was cooled at room temperature and 20 ml of 10% potassium hydroxide in methanol were added. After 1 hour 500 ml of 5% aqueous NaCI were added and the precipitated product was isolated by filtration and dried. After crystallization from acetonitrile, 8 g of pure 10a-methoxy_- lumilysergol having the following chemical and physical characteristics were obtained:

m.p.: 180―182°C; [α]

(methanol) = +8.95; M⁺: 286.

Example 2

10a-methoxy-lumilysergol

[0019] 2.96 g of lysergol 8-acetate were dissolved in 100 ml of a mixture of 4.5% w/v of concentrated sulphuric acid in methanol previously cooled to -30°C. The solution, kept at a temperature of -20°C and under nitrogen, was irradiated by a UV lamp emitting at 330 nm for about 2 hours. When the reaction was complete, the cooling was stopped and the solution was slowly brought to a temperature of +30°C, which was maintained for 3 hours. The reaction mixture was diluted with 150 ml of water and made alkaline with NH₄0H to pH 8.5.

[0020] The hydromethanolic solution was extracted six times with 50 ml of methylene chloride. The organic phase, after dehydration over Na₂S0₄, was concentrated to dryness in vacuo and the residue was crystallized from methanol.

[0021] The product was 2.75 g of pure 10a-methoxylumilysergol having the following chemical and physical characteristics:

m.p.: 180-182°C; [α]²⁰_D (methanol) = +8.95; M⁺: 286.

Example 3

1-methyl-10a-methoxy-lumilysergol 8-methane sulphonate

[0022] (a) 10 g of lysergol 8-methane sulphonate was irradiated as described in Example 1, and after 2 hours of irradiation, while always maintaining the temperature at about -20°C, 250 g of ice was added and the mixture was brought to pH 8.5 with NH₄0H. The resulting solution was extracted with 6 x 100 ml of CH₂CI₂; the combined extracts were dried over Na₂SO₄ and concentrated to dryness.

[0023] The product was 8.5 g of 10-methoxy lumilysergol 8-methane sulphonate, sufficiently pure for the subsequent reactions.

[0024] (b) 0.78 g of metallic potassium and 0.04 g ferric nitrate were dissolved in 250 ml of liquid ammonia a multi-necked 500 ml flask cooled to -60°C. When dissolution was complete, 3.5 g of 10-methoxy lumilysergol 8-methane sulphonate and 1.45 g of methyl iodide were added. The reaction was kept at the same temperature for 3 hours, after which 1.5 g of ammonium chloride were added and distillation of ammonia began. The residue was dissolved in 20 ml cold methanol containing 1% acetic acid and the solution was diluted with 25 ml H₂0. The resulting solution was made alkaline at pH 8.5 and extracted twice with 20 ml of methylene chloride.

[0025] The chlorinated extracts were concentrated to dryness and the residue was recrystallized from acetonitrile, obtaining 3.3 g of pure product.

Example 4

1-methyl-10α-methoxy-lumilysergol 8-(5-bromo-nicotinate)

[0026] 3.85 g of 1-methyl-10a-methoxy-lumilysergol 8-methane sulphonate, obtained as in Example 2, was dissolved in 20 ml of dimethyl formamide; 5 g of potassium 5-bromonicotinate were added to the solution and the mixture was kept under agitation at 40°C for 4 hours. The solution was poured on to crushed ice, giving a suspension which was extracted with methylene chloride. The organic phase, carefully washed with water so as to eliminate dimethyl formamide, was concentrated to reduce the volume and the product was recrystallized from ether. The product was 4.7 g of 1-methyl-10a-methoxy lumilysergol 8-(5-bromonicotinate) having the following characteristics:

m.p.: 138-139°C; [α]

= -20 (c=₁, Py); +20 (c=5, CHCI₃).

Claims

1. A method of preparing a lysergol derivative of formula (I)

in which

R¹ represents hydrogen or methyl, and

-OR² represents a free or esterified hydroxyl group

characterised in that a lysergol ester of formula (VII)

in which -OR³ represents an esterified hydroxyl group is subjected to photo-chemical reaction by irradiating with UV light of wavelength from 300 to 370 nm at a temperature below 0°C in methanol containing from to 10% (w/v) of H₂S0₄ to produce an ester of 10a-methoxy lumilysergol of formula (VIII)

and the resulting ester of 10α-methoxy lumilysergol of formula (VIII) is converted to a compound of formula (I) by one or more of the following optional steps carried out in any appropriate order:

(a) N-methylation;

(b) hydrolysis to form a compound in which OR² represents hydroxyl;

(c) esterification of a compound in which OR² represents hydroxyl to form a compound in which OR² represents an esterified hydroxyl group;

(d) transesterification of a compound in which OR² represents an esterified hydroxyl group.

2. A method according to Claim 1 wherein the photo-chemical reaction is carried out by irradiating with UV light of wavelength of 330 nm.

3. A method according to Claim 1 or Claim 2 wherein prior to step (a) a compound of formula (VIII) in which OR³ is an esterified hydroxyl group is isolated at a temperature below 0°C by neutralisation with base, dilution with water and solvent extraction.

4. A method according to Claim 3 characterised in that the compound of formula (VIII) is isolated at temperatures below -10°C.

5. A method according to any preceding claim wherein step (a) is carried out by contacting a resulting compound of formula (VIII) with methyl iodide and potassium in liquid ammonia.

6. A method according to any preceding claim in which R² and R³ represents alkyl- or aryl-sulphonyl groups or R-CO radicals in which R represents an unsubstituted or halogen-substituted alkyl, aryl or alkaryl group.

7. A method according to any preceding claim characterised in that the photo-chemical reaction is carried out at a temperature between -10 and -30°C.

8. A method according to any preceding claim characterised in that the concentration of H₂SO₄ in methanol is 3% w/v.

9. A method according to any preceding claim characterised in that the transesterification is carried out using alkali-metal carboxylates in dimethyl formamide or dimethyl sulphoxide.

10. A method according to any preceding claim characterised in that R³ represents methane-sulphonyl.

11. A method according to any preceding claim characterised in that R² represents 5-bromo-nicotinoyl.

Ansprüche

1. Verfahren zur Herstellung eines Lysergolderivats der Formel (I)

worin R¹ Wasserstoff oder Methyl ist und -OR² eine freie oder veresterte Hydroxylgruppe bedeutet, dadurch gekennzeichnet, daß ein Lysergolester der Formel (VII)

worin -OR³ eine veresterte Hydroxylgruppe ist, einer photochemischen Reaktion durch Bestrahlung mit Ultraviolettlicht mit einer Wellenlänge von 300 bis 370 nm bei einer Temperatur von unter 0°C in Methanol, das 2 bis 10 Prozent (Gewicht/Volumen) H₂S0₄ enthält, unter Bildung eines Esters von 10a-Methoxy- lumilysergol der Formel (VIII)

unterzogen wird, und daß der erhaltene Ester von 10a-Methoxy-lumilysergol der Formel (VIII) durch Anwendung einer oder mehrerer der im folgenden angegebenen Stufen in irgendeiner geeigneten Reihenfolge in eine Verbindung der Formel (I) überführt wird:

a) N-Methylierung,

b) Hydrolyse unter Bildung einer Verbindung, worin -OR² Hydroxyl ist,

c) Veresterung einer Verbindung, worin -OR² Hydroxyl bedeutet, unter Bildung einer Verbindung, worin -OR² eine versterte Hydroxylgruppe ist, oder

d) Umesterung einer Verbindung, worin -OR² eine veresterte Hydroxylgruppe ist.

2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß die photochemische Reaktion durch Bestrahlung mit Ultraviolettlicht mit einer Wellenlänge von 330 nm durchgeführt wird.

3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß vor der Stufe (a) eine Verbindung der Formel (VIII), worin―OR³ eine veresterte Hydroxylgruppe ist, bei einer Temperatur von unter 0°C durch Neutralisation mit Base, Verdünnung mit Wasser und Extraktion mit einem Lösungsmittel isoliert wird.

4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß die Verbindung der Formel (VIII) bei einer Temperatur von unter -10°C isoliert wird.

5. Verfahren nach irgendeinem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Stufe (a) durch Umsetzung einer Verbindung der Formel (VIII) mit Methyliodid und Kalium in flüssigem Ammoniak durchgeführt wird.

6. Verfahren nach irgendeinem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Substituenten R² und R³ Alkylsulfonylgruppen, Arylsulfonylgruppen oder Reste R-CO sind, worin R eine unsubstituierte oder eine halogensubstituierte Alkylgruppe, Arylgruppe oder Alkarylgruppe ist.

7. Verfahren nach irgendeinem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die photochemische Reaktion bei einer Temperatur zwischen -10°C und -30°C durchgeführt wird.

8. Verfahren nach irgendeinem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Konzentration von H₂S0₄ in Methanol 3 Prozent (Gewicht/Volumen) beträgt.

9. Verfahren nach irgendeinem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Umesterung unter Anwendung von Alkalimetallcarboxylaten in Dimethylformamid oder Dimethylsulfoxid durchgeführt wird.

10. Verfahren nach irgendeinem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß R³ für Methansulfonyl steht.

11. Verfahren nach irgendeinem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß R² für 5-Bromnicotinoyl steht.

Revendications

1. Procédé pour préparer un dérivé de lysergol de formule (I)

dans laquelle

R' représente un hydrogène ou un méthyle, et

―OR² représente un groupe hydroxyle libre ou estérifié,

caractérisé en ce que l'on soumet un ester de lysergol de formule (VII)

dans laquelle-OR³ représente un groupe hydroxyle estérifié, à une réaction photochimique par irradiation avec une lumière ultraviolette ayant une longueur d'onde de 300 à 370 nm à une température inférieure à 0°C dans du méthanol contenant de 2 à 10% (p/v) d'H₂S0₄ pour produire un ester de 10a-méthoxylumilysergol de formule (VIII)

et on transforme l'ester de 10a-méthoxylumilysergol obtenu de formule (VIII) en un composé de formule (I) selon un ou plusieurs des stades facultatifs suivants effectués dans un ordre approprié quelconque:

(a) N-méthylation;

(b) hydrolyse pour former un composé dans lequel OR² représente un hydroxyle;

(c) estérification d'un composé dans lequel OR² représente un hydroxyle pour former un composé dans lequel OR² représente un groupe hydroxyle estérifié;

(d) transestérification d'un composé dans lequel OR² représente un groupe hydroxyle estérifié.

2. Procédé selon la revendication 1, dans lequel la réaction photochimique est effectuée par irradiation avec une lumière ultraviolette ayant une longueur d'onde de 330 nm.

3. Procédé selon la revendication 1 ou la revendication 2, dans lequel, avant le stade (a), on isole un composé de formule (VIII) dans laquelle OR³ est un groupe hydroxyle estérifié, à une température inférieure à 0°C, par neutralisation avec une base, dilution avec de l'eau et extraction avec un solvant.

4. Procédé selon la revendication 3, caractérisé en ce qu'on isole le composé de formule (VIII) à des températures inférieures à -10°C.

5. Procédé selon l'une quelconque des revendications précédentes, dans lequel le stade (a) est effectué par contact d'un composé obtenu de formule (VIII) avec de l'iodure de méthyle et du potassium dans l'ammoniac liquide.

6. Procédé selon l'une quelconque des revendications précédentes, dans lequel R² et R³ représentent des groupes alcoyl- ou aryl-sulfonyles ou des radicaux R-CO dans lesquels R représente un groupe alcoyle, aryle ou alcaryle non substitués ou halogéno-substitués.

7. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que la réaction photochimique est effectuée à une température entre -10 et -30°C.

8. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que la concentration de l'H₂S0₄ dans le méthanol est de 3% p/v.

9. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que la transestérification est effectuée par utilisation de carboxylates de métaux alcalins dans le diméthylformamide ou le diméthylsulfoxyde.

10. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que R³ représente un méthanesulfonyle.

11. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que R² représente un 5-bromonicotinoyle.